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  • Updated 05.14.2024
  • Released 12.28.1993
  • Expires For CME 05.14.2027

Globoid cell leukodystrophy



Globoid cell leukodystrophy, or Krabbe disease, is an autosomal recessive, rapidly progressive fatal disease when it occurs in infancy. The disease usually begins between the ages of 3 and 6 months with ambiguous symptoms, such as irritability or hypersensitivity to external stimuli, but soon progresses to severe mental and motor decline. Patients are initially hypertonic with hyperactive reflexes, but they later become flaccid and hypotonic. Blindness and deafness are common. Patients with late-onset forms, including adult-onset, may present with blindness, spastic paraparesis, and dementia. Saposin A deficiency is a rare cause of Krabbe disease. Brain MRI has characteristic features that depend on the age of onset of the disease (infantile, juvenile, or adult). Optic nerve and cauda equina enlargement and enhancement are common, as is midbrain atrophy. The presence of peripheral nerve enlargement detected by ultrasound strongly supports the diagnostic possibility of Krabbe disease (58). Newborn screening and presymptomatic hematopoietic stem cell transplantation have not yielded clear benefits.

Key points

• Globoid cell leukodystrophy may occur at any age, but the infantile type is the most common.

• Typical MRI changes that vary according to each phenotype suggest the diagnosis.

• The adult-onset type is the most prevalent in certain populations, such as Japan.

• Hematopoietic stem cell transplantation in presymptomatic infants only mitigates the disease and is not the optimal therapy it was once hoped to be.

• Measuring psychosine, a major offending metabolite in Krabbe disease, in dried blood spots helps in diagnosis and differentiation of infantile from later onset variants and in monitoring of disease progression and response to treatment.

Historical note and terminology

Globoid cell leukodystrophy, or Krabbe disease, was described in 1916. Danish neurologist Knud Haraldsen Krabbe (1885-1961) reported the clinical and neuropathologic description of five cases that appeared to represent a new disease entity (54).

Danish neurologist Knud Haraldsen Krabbe (1885-1961)

In 1916, Krabbe first described what is now known as globoid cell leukodystrophy or Krabbe disease. (Courtesy of the US National Library of Medicine. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativec...

Previous neuropathologic studies by American neuropathologist William Norton Bullard (1853-1931) and American neuropsychiatrist and neuropathologist Elmer Ernest Southard (1876-1920), working at Boston City Hospital in 1906, and German pathologist Rudolf Beneke (1861-1946) in 1908, however, had already described the "diffuse gliosis" of brain that was later characterized as "diffuse brain-sclerosis" in Krabbe patients (11; 08).

In 1924, English neurologist James Stansfield Collier (1870-1935) and Scottish neuropathologist Joseph Godwin Greenfield (1885-1958) used the term "globoid cells" to describe the phagocytic cells that appeared to be unique to this disorder (21). German neuropathologist Julius Hallervorden (1882-1965), a former member of the Nazi Party (ie, the National Socialist German Workers' Party) who had knowingly performed much of his research on the brains of executed prisoners and participated in the action T4 euthanasia program, suggested that these globoid cells may contain kerasin or cerebroside (36).

German pathologist Julius Hallervorden (1882-1965)

Hallervorden was a former member of the Nazi Party (ie, the National Socialist German Workers' Party) who had knowingly performed much of his research on the brains of executed prisoners and participated in the action T4 euthan...

Biochemical and histochemical studies confirmed the presence of cerebroside in globoid cells (09; 05), and galactocerebroside was the only glycolipid that could produce globoid cells when injected into the central nervous system of experimental animals (03). Analytical biochemical studies of total brain lipids did not show an increase in galactosylcerebroside in this disease, but rather a lowering of total cerebroside and sulfatide and a reduced sulfatide-to-cerebroside ratio (95). Only a fraction of brain lipids enriched in the specialized globoid cells showed increased galactosylceramide (05). In 1970, Malone reported a deficiency of leukocyte galactosylceramide beta-galactosidase in a Krabbe disease patient (68); this was confirmed by Suzuki and Suzuki, who demonstrated the enzyme deficiency in the brain, liver, and spleen of three patients with Krabbe disease (93). Psychosine, a related glycolipid, was suggested to be the toxic metabolite responsible for the pathogenesis of this disorder (71; 92). The gene for the galactosylceramidase (GALC) enzyme has been mapped to chromosome 14 (113), and the cDNA has been cloned by Chen and colleagues (17).

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